Methemoglobin formation

Inhalation is the chief route of worker exposure. Comparative data from acute or subchronic inhalation exposures with rats (98) indicate that nitromethane and nitroethane are the least toxic of the nitroparaffins by this route and do not induce methemoglobin formation. The nitropropanes are less well tolerated 2-nitropropane is more toxic than 1-nitropropane and is more likely to cause methemoglobinemia. 

Aniline is lipophilic (pKa of 4.6) and is expected to be rapidly and completely absorbed in the small intestine (Kao et al. 1978). No information on relative bioavailability following inhalation exposure was located, but as indicated by methemoglobin formation during inhalation experiments, systemic absorption by both the inhalation and the percutaneous routes is extensive. Percutaneous absorption of aniline in hairless mice was 4.7% of the nominal applied doses (Susten et al. 1990). 

O Neal, F.O. 1982. Subacute inhalation toxicity of aniline The relationship between methemoglobin formation and toxicity. Toxicologist 2 164. 

Spicer, S.S. 1950. Species differences in susceptibility to methemoglobin formation. J. Pharmacol. Exp. Ther. 99 185-194. 

Interspecies 10—A review of oral administration studies suggested that humans may be considerably more sensitive to methemoglobin formation than rats. Oral administration of aniline to rats at 40 mg/kg produced a maximum increase of 16.6% in methemoglobin, whereas oral administration of 0.9 mg/kg to a human volunteer produced a maximum increase of 16.1%. ... 

Time Scaling Cnxt=k, where n=l and k=480 ppm-min based on the linear relationship between concentration and methemoglobin formation (Kim and Carlson... 

Test Species/Strain/Sex/Number Adult male Sprague-Dawley rats, 5/exposure group Exposure Route/Concentrations/Durations 0-150 ppm for 8 h Effects Concentration (ppm) Methemoglobin Formation (%)a... 

The primary function of the mammalian red blood cell is to maintain aerobic metabolism while the iron atom of the heme molecule is in the ferrous (Fe+2) oxidation state however, copper is necessary for this process to occur (USEPA 1980). Excess copper within the cell oxidizes the ferrous iron to the ferric (Fe+3) state. This molecule, known as methemoglobin, is unable to bind oxygen or carbon dioxide and is not dissociable (Langlois and Calabrese 1992). Simultaneous exposure of sheep to mixtures of cupric acetate, sodium chlorite, and sodium nitrite produced a dose-dependent increase in methemoglobin formation (Calabrese et al. 1992 Langlois and Calabrese 1992). 

Calabrese, E.J., J.A. Garreffi, and E.J. Stanek. 1992. The effects of joint exposures to environmental oxidants on methemoglobin formation copper/nitrate and copper/chlorite. Jour. Environ. Sci. Health 27A 629-642. 

Wyman, J.F., B.H.Gray, L.H.Hill, J.Coleman, C.Flemming, and D.E.Uddin. 1985. Interspecies variability in propylene glycol dinitrate-induced methemoglobin formation. Toxicol. Appl. Pharmacol. 81 203-212. 

Sun et al. (1995) reported that the nitric oxide generator, isosorbide dinitrate, is an effective cyanide antidote in mice. They showed that the mechanism does not involve methemoglobin formation and suggested that nitric oxide might antagonize the respiratory depressant effects of cyanide. Other more efficient nitric oxide generators may be very useful cyanide antidotes. 

The role of deacetylation in methemoglobinemia induced by acetanilide (4.101) and phenacetin (4.107) has been demonstrated. Indeed, concomitant i.p. administration of BNPP considerably reduced the hematotoxicity of these compounds [87]. Recent studies have shown that /V-hydroxyphenetidine (4.144), a metabolite of deacetylated phenacetin, is responsible for hemolysis and methemoglobin formation [88]. 

Takeoka S, Sakai H, Kose T, et al. Methemoglobin formation in hemoglobin vesicles and reduction by encapsulated thiols. Bioconjug Chem 1997 8 539. 

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